Psoralen plus long wavelength ultraviolet radiation (UV-A) is being investigated as a model system for clinically relevant photochemical carcinogenesis and as a probe for defective DNA repair. Used experimentally for treatment of psoriasis and mycosis fungoides, psoralen plys UV-A has been found to be mutagenic, carcinogenic and immunosuppressive. We developed an in vitro assay to measure the effects of UV-A mediated psoralen-DNA binding in human lymphoid cells. Parameters monitored include the rate of DNA synthesis, induction of DNA-psoralen cross-links, induction of sister chromatid exchanges, alterations in the rate of cell proliferation and survival, and in immune reactivity. These studies indicate that the low doses of psoralen plus UV-A received by patients' leukocytes during therapy may result directly in decreased DNA synthesis in their circulating lymphoid cells. Cell survival was found to be markedly dependent on UV-A exposure and 8-MOP concentration, to be correlated with inhibition of DNA synthesis, and to be related to induction of DNA interstrand cross-links. There was a dose-dependent reduction in mixed leukocyte culture reactivity induced by 8-MOP plus UV-A treatment. Pathways for repair of psoralen DNA damage were examined by studying cells from a patient with the genetic disease, Cockayne's syndrome. Cells from a patient with Cockayne's syndrome had a normal survival following 8-MOP plus UV-A treatment, but reduced survival after treatment with UV-A. Thus repair of photosensitized 8-MOP damage involves at least one pathway that is different from that for UV-A damage.